The goal of this project is to evaluate the effects of sigma-1 receptor (S1R) activation on RGCs and optic nerve head astrocytes (ONHAs) under glaucomatous conditions. Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by the progressive degeneration of retinal ganglion cells (RGCs). The major risk factor for glaucoma is increased intraocular pressure (IOP), and lowering IOP is currently the only treatment strategy for this disease. However, in many cases, decreasing IOP does not effectively prevent glaucomatous vision loss. Thus, novel therapies are needed. Activation of the multifunctional sigma 1 receptor (S1R) is a promising pluripotent target for glaucoma treatment. S1R stimulation provides robust RGC protection, both in vitro and in vivo, but it has not been tested in glaucoma. In addition, the mechanisms of S1R-mediated neuroprotection are not well understood. S1R is a ligand-operated, transmembrane protein that is expressed in RGCs and astrocytes throughout the visual system. A major deficit in our understanding of S1R is knowledge of its direct effects on glia cells and how these effects mediate glia-neuronal interactions. Astrocytes are the major glial constituent of the optic nerve head (ONH), which is the site of initial glaucomatous injury. At the ONH, astrocytes play a critical role in maintaining the health of RGC axons. Our preliminary data indicates that agonists of S1R can protect RGCs through cell autonomous effects on RGCs themselves and through non-cell autonomous effects on optic nerve head astrocytes (ONHAs). We find evidence that activation of S1R in ONHAs suppresses astrocyte reactivity and increases release of brain derived neurotrophic factor (BDNF). In addition, previous studies show that S1R agonists not only protect neurons from injury, but also enhance neuronal plasticity and restore neuronal function. In this proposal, we will test the hypothesis that S1R agonists shift the balance of ONHA-mediated support functions in favor of RGC protection. Thus, treatment of ocular hypertensive rats with S1R agonists is proposed to prevent and restore structural and functional deficits in experimental glaucoma. To test our central hypothesis we propose three specific aims: Aim 1: Test the hypothesis that S1R agonists slow progression and rescue structural and functional deficits in experimental glaucoma. Aim 2: Test the hypothesis that S1R directly mediates ONHA reactivity and trophic factor secretion. Aim 3: Test the hypothesis that S1R activation in ONHAs provides neuroprotection for RGCs. .